Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease

ABSTRACT

The invention relates to pimobendan for use in a method of reducing the heart size and/or delaying the onset of clinical symptoms in a patient suffering from asymptomatic (occult, preclinical) heart failure, preferably congestive heart failure, due to mitral valve disease (MVD), and/or delaying the onset of heart failure, preferably congestive heart failure, in a patient suffering from asymptomatic (occult, preclinical) heart failure, preferably congestive heart failure, due to mitral valve disease (MVD), wherein the patient is preferably a mammal, more preferably a human, a dog, a cat or a horse, and most preferably a dog.

FIELD OF THE INVENTION

The invention relates to the field of medicine, particularly veterinarymedicine. In particular, the invention relates to the use of pimobendanfor the reduction of heart size in patients with asymptomatic (occult,preclinical) heart failure (HF) due to (myxomatous) mitral valve disease[(M)MVD] and/or chronic valvular heart disease (CVHD; also known aschronic valve disease, CVD) and/or atrial ventricular valvularinsufficiency (AVVI) and/or for the delay of onset of clinical symptomsin patients with asymptomatic (occult, preclinical) HF due to (m)MVDand/or CVHD/CVD and/or AVVI, and/or the delay of onset of heart failuredue to (myxomatous) mitral valve disease [(M)MVD] and/or chronicvalvular heart disease (CVHD; also known as chronic valve disease, CVD)and/or atrial ventricular valvular insufficiency (AVVI).

BACKGROUND OF THE INVENTION

Heart failure is divided in different stages, which were defined bydifferent classification systems, e.g. the International Small AnimalCardiac Health Council (ISACHC), the New York Heart Association (NYHA)functional classification systems and the currently used classificationaccording to the Consensus Statements of the American College ofVeterinary Internal Medicine (ACVIM), 2009.

Classification according to the International Small Animal CardiacHealth Council (ISACHC) System:

Class I: asymptomatic (also known as occult or preclinical)

Class IA: no evidence of compensation for underlying heart disease (novolume overload or pressure overload detected radiographically orechocardiographically)

Class IB: clinical signs of compensation for underlying heart disease(volume overload or pressure overload detected radiographically orechocardiographically)

Class II: mild to moderate heart failure with clinical signs at rest orwith mild exercise (treatment required)

Class III: advanced heart failure; clinical signs of severe congestiveheart failure

Class IIIA: home treatment possible

Class IIIB: requires hospitalization

New York Heart Association (NYHA) functional classification system:

Class I: describes patients with asymptomatic heart disease (e.g.,chronic valvular heart disease (CVHD) is present, but no clinical signsare evident even with exercise).

Class II: describes patients with heart disease that causes clinicalsigns only during strenuous exercise.

Class III: describes patients with heart disease that causes clinicalsigns with routine daily activities or mild exercise.

Class IV: describes patients with heart disease that causes severeclinical signs even at rest.

The ACVIM system describes four basic stages of heart disease andfailure:

-   Stage A: patients at high risk for developing heart disease but that    currently have no identifiable structural disorder of the heart    (e.g., every Cavalier King Charles Spaniel without a heart murmur).-   Stage B: patients with structural heart disease (e.g., the typical    murmur of mitral valve regurgitation is present), but that have    never developed clinical signs caused by heart failure (because of    important clinical implications for prognosis and treatment, the    panel further subdivided Stage B into Stage B1 and B2).-   Stage B1: asymptomatic patients that have no radiographic or    echocardiographic evidence of cardiac remodeling in response to    CVHD.-   Stage B2: asymptomatic patients that have hemodynamically    significant valve regurgitation, as evidenced by radiographic or    echocardiographic findings of left-sided heart enlargement.-   Stage C: patients with past or current clinical signs of heart    failure associated with structural heart disease.-   Stage D: patients with end-stage disease with clinical signs of    heart failure caused by CVHD that are refractory to “standard    therapy”.

The pathology of the heart begins with ISACHC Class I, NYHA Class I andACVIM stage B2 in which cardiac murmur or cardiac chamber enlargement,but no clinical symptoms are present (ISACHC Class I orasymptomatic/occult/preclinical stage). Clinical symptoms becomemanifest in the course of progression of the disease (ISACHC Class II orIII, NYHA class II, III or IV, ACVIM stage C and D).

Known progression of (M)MVD or CVHD/CVD or AVVI heart failure isassociated with an increase of the heart size. Cardiac remodeling due tothe morphologic changes within the heart is generally considered as arisk factor and is linked to worsening of pathophysiologic changes ofthe heart leading to heart failure. One goal of the therapy of heartfailure is the reduction of the heart size and the delay ofmorphological changes of the heart.

A known pharmaceutically active compound to treat heart failure ispimobendan(4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone)disclosed in EP 0 008 391 and having the formula:

Pimobendan is a well-known compound for the treatment of congestiveheart failure (CHF) originating for example from dilated cardiomyopathy(DCM) or mitral valve disease (MVD) in animals, especially dogs.Pimobendan is also approved as a drug product for cardiovasculartreatment in humans in Japan.

Several publications disclose the use of pimobendan in the treatment ofheart failure in animals, such as, for instance, the following ones.

WO 2005/092343 describes the use of PDE-III inhibitors, such aspimobendan, for the reduction of heart size of a patient suffering fromheart failure without, however, mentioning patients with asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD).

Lombard and co-workers (Lombard C W et al., J Am Anim Hosp Assoc 2006,42: 249-261) disclose the clinical efficacy of pimobendan versusbenazepril for the treatment of the clinical acquired atrioventricularvalvular disease in dogs.

WO 2007/054514 is directed to the use of PDE-III inhibitors, such aspimobendan, for the treatment of asymptomatic (also known as occult orpreclinical) heart failure without, however, mentioning patients withasymptomatic (occult, preclinical) heart failure due to mitral valvedisease (MVD).

Häggström J et al. (J Vet Intern Med 2008, 22: 1124-1135) describe theeffect of pimobendan or benazepril hydrochloride on survival times indogs with clinical congestive heart failure caused by naturallyoccurring myxomatous mitral valve disease without, however, mentioningpatients with asymptomatic (occult, preclinical) heart failure due tomitral valve disease (MVD).

Summerfield N J and co-workers (Summerfield N J et al., J Vet Intern Med2012, 26: 1337-1349) relate to a clinical study on the efficacy ofpimobendan in the prevention of congestive heart failure or sudden deathin Doberman Pinschers with preclinical dilated cardiomyopathy (DCM).However, they are silent about patients with asymptomatic (occult,preclinical) heart failure due to mitral valve disease (MVD).

Häggström J et al. (J Vet Intern Med 2013, 27: 1452-1462) describeshort-term hemodynamic and neuroendocrine effects of pimobendan andbenazepril in dogs with clinical myxomatous mitral valve disease andcongestive heart failure. However, they are silent about patients withasymptomatic (occult, preclinical) heart failure due to mitral valvedisease (MVD).

Internet website www.epictrial.com is directed to the EPIC trial, astudy to investigate the effects of pimobendan in the delay of onset ofclinical symptoms of congestive heart failure due to mitral valvedisease (MVD). However, at the priority dates of this patent applicationthis trial was still ongoing and no study results were publicallyavailable.

Several other publications, however, relate to the disadvantageouscardiac effects of pimobendan treatment, such as the following ones.

Schneider P et al. (Exp Toxic Pathol 1997, 49: 217-224) describe thecomparative cardiac toxicity of the IV administered pimobendan in femaleBeagle dogs.

Tissier R and co-workers (Tissier R et al., Cardiovascular Toxicology2005, 5(1): 43-51) disclose adverse effects increased mitral valveregurgitation and myocardial hypertrophy in two dogs with long-term(chronic) clinical pimobendan therapy.

Amsallem E et al. (Cochrane Database Syst Rev 2005, 25: 1) found thatphosphodiesterase inhibitors, such as among others pimobendan, areassociated with a significant 17% increased mortality rate in humanpatients and in addition significantly increase cardiac death, suddendeath, arrhythmias and vertigos. The authors conclude that chronic useof phosphodiesterase inhibitors should be avoided in heart failurepatients.

Chetboul V and co-workers (Chetboul V et al., J Vet Intern Med 2007, 21:742-753) show the results of a prospective, controlled, blinded andrandomized study on the comparative adverse cardiac effects ofpimobendan and benazepril monotherapy in dogs with mild degenerativeasymptomatic mitral valve disease.

Ouellet M et al. (J Vet Intern Med 2009, 23: 258-263) describe theeffect of pimobendan on echocardiographic values in dogs withasymptomatic mitral valve disease. However, this study failed toidentify beneficial long-term changes in the severity of mitralregurgitation after addition of pimobendan to ACE inhibitor treatment.

The objective underlying the present invention is, therefore, to providea medical treatment which overcomes the problems of the prior art asdescribed above.

SUMMARY OF THE INVENTION

The present invention concerns pimobendan for use in a method ofreducing the heart size and/or delaying the onset of clinical symptomsin a patient suffering from asymptomatic (occult, preclinical) heartfailure due to mitral valve disease (MVD), preferably asymptomatic(occult, preclinical) congestive heart failure due to mitral valvedisease (MVD), more preferably asymptomatic (occult, preclinical)congestive heart failure due to myxomatous mitral valve disease (MMVD),and/or delaying the onset of heart failure in a patient suffering fromasymptomatic (occult, preclinical) heart failure due to mitral valvedisease (MVD), preferably delaying the onset of congestive heart failurein a patient suffering from asymptomatic (occult, preclinical) heartfailure due to mitral valve disease (MVD), more preferably delaying theonset of congestive heart failure in a patient suffering fromasymptomatic (occult, preclinical) heart failure due to myxomatousmitral valve disease (MMVD).

Corresponding methods of reducing the heart size and/or delaying theonset of clinical symptoms in a patient suffering from asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD)and/or delaying the onset of (congestive) heart failure in a patientsuffering from asymptomatic (occult, preclinical) heart failure due tomitral valve disease (MVD) and uses for the preparation of apharmaceutical composition/medicament for reducing the heart size and/ordelaying the onset of clinical symptoms in a patient suffering fromasymptomatic (occult, preclinical) heart failure due to mitral valvedisease (MVD) and/or delaying the onset of heart failure, preferablycongestive heart failure, in a patient suffering from asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD)are also intended to be within the scope of the present invention.

The present invention further concerns pimobendan for use in a method ofreducing the heart size and delaying the onset of clinical symptoms in apatient suffering from asymptomatic (occult, preclinical) heart failuredue to mitral valve disease (MVD), preferably asymptomatic (occult,preclinical) congestive heart failure due to mitral valve disease (MVD),more preferably asymptomatic (occult, preclinical) congestive heartfailure due to myxomatous mitral valve disease (MMVD), and delaying theonset of heart failure in a patient suffering from asymptomatic (occult,preclinical) heart failure due to mitral valve disease (MVD), preferablydelaying the onset of congestive heart failure in a patient sufferingfrom asymptomatic (occult, preclinical) heart failure due to mitralvalve disease (MVD), more preferably delaying the onset of congestiveheart failure in a patient suffering from asymptomatic (occult,preclinical) heart failure due to myxomatous mitral valve disease(MMVD).

Corresponding methods of reducing the heart size and delaying the onsetof clinical symptoms in a patient suffering from asymptomatic (occult,preclinical) heart failure due to mitral valve disease (MVD) and/ordelaying the onset of (congestive) heart failure in a patient sufferingfrom asymptomatic (occult, preclinical) heart failure due to mitralvalve disease (MVD) and uses for the preparation of a pharmaceuticalcomposition/medicament for reducing the heart size and delaying theonset of clinical symptoms in a patient suffering from asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD)and delaying the onset of heart failure, preferably congestive heartfailure, in a patient suffering from asymptomatic (occult, preclinical)heart failure due to mitral valve disease (MVD) are also intended to bewithin the scope of the present invention.

The advantages of the medical use(s) of pimobendan according to thepresent invention are as follows:

-   -   Prolongation of the preclinical (also known as asymptomatic or        occult) phase without exhibiting clinical symptoms of congestive        heart failure    -   Delay of onset of (clinical symptoms of) congestive heart        failure    -   Increase of survival time of the treated patients as compared to        placebo treatment    -   Improvement of the quality of life of the treated patients    -   Reduction of heart size of the treated patients as compared to        baseline (i.e. before start of treatment)    -   Improving cardiac function/output in the treated patients    -   Reduction of sudden cardiac death/euthanasia of patients due to        cardiac reasons    -   Risk reduction of reaching congestive heart failure

Any previously raised concerns regarding the safety of the medicationshould be allayed by the longer survival observed in the pimobendangroup in the all-cause mortality analysis. There was no differencebetween groups in the rate or type of potential adverse events observed.This is despite the fact that dogs in the pimobendan group spent longertime in the study and were therefore at risk of experiencing adverseevents for a longer period.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetails it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

The term “patient” as used hereinabove and herein below relates to ananimal or a person suffering from (congestive) heart failure. The term“patient” embraces mammals such as primates including humans. Inaddition to primates, a variety of other mammals can be treatedaccording to the method of the present invention. For instance, mammals,including but not limited to, horses, dogs, cats, or equine, canine,feline species can be treated. Preferred are human patients, dogs, catsand horses. Human patients are female or male person who are sufferingfrom heart failure. As a rule such persons are children, young adults,adults or elderly people with an age of between 6 and 80, preferablybetween 30 and 65 years. Most preferred are dogs.

The term heart failure”, preferably “congestive heart failure”, as usedhereinabove and herein below relates to any contractile disorder ordisease of the heart. Clinical manifestations are as a rule the resultsof changes to the heart's cellular and molecular components and tomediators that drive homeostatic control. The heart failure, preferablycongestive heart failure, is as a rule accompanied by an increase of theheart size and deterioration of cardiac functions.

The term “reduction of the heart size” as used hereinabove and hereinbelow relates to a reduction of the size of the heart of the patient,which is diagnosed using echocardiography and which may be determinedaccording to the radiograph methods suggested by James W. Buchanan etal. (Buchanan J W et al., J Am Vet Med Assoc 1995, 206(2), 194-199) andis expressed in the relative change of the vertebral heart size.Preferably, the relative heart size of said patient is reduced by atleast 5%, preferably at least 10%, 15%, 20%, 25% or at least 30%,compared to baseline, i.e. before pimobendan treatment is initiated,more preferably within 10 to 100 days, even more preferably within about30 to 40 days, most preferably within about 35 days of treatment withpimobendan.

The term “asymptomatic (occult, preclinical) (congestive) heart failuredue to mitral valve disease (MVD)” as used hereinabove and herein belowrelates to any contractile disorder or disease of the heart which is dueto/secondary to MVD—however, yet without any clinical symptoms of(congestive) heart failure. In particular, it relates to heart failureof ISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIMstage B2.

The terms “delay of onset of clinical symptoms” and “prolongation oftime until onset of clinical symptoms” are interchangeably usedhereinabove and herein below and relate to the time period between fromdiagnosing the morphological changes of the heart of the patient untilthe beginning of clinical symptoms of heart failure, preferablycongestive heart failure, due to mitral valve disease (MVD). Inparticular, they relate to the prolongation of time from stillasymptomatic (occult, preclinical) heart failure of ISACHC Class I(Class IA and/or Class IB), NYHA Class I and ACVIM stage B2 to clinicalevident heart failure, preferably congestive heart failure, of ISACHCClass II and further to Class III (Class IIIA and/or Class IIIB), NYHAClass II, III and IV and ACVIM stage C and D.

For the sake of unambiguity in the course of the present invention themedicinal indication terms “mitral valve disease (MVD)”, “myxomatousmitral valve disease (MMVD)”, “chronic valvular heart disease (CVHD)”,“chronic valve disease (CVD)” and “atrial ventricular valvularinsufficiency (AVVI)” are all interchangeably used. As for ISACHC ClassI (Class IA and/or Class IB), NYHA Class I and ACVIM stage B2 heartfailure they are all synonymous to each other and have the identicalmedicinal meaning.

The term “risk reduction of reaching congestive heart failure” as usedhereinabove and herein below relates to the relative risk ofexperiencing the clinical evident heart failure, preferably congestiveheart failure. Preferably, the relative risk is reduced by at least 5%,preferably at least 10%, 15%, 20%, 25% or at least 30%.

The term “effective amount” as used herein means an amount sufficient toachieve a reduction of the heart size in patients with asymptomatic(occult, preclinical) heart failure (HF) due to mitral valve disease(MVD) and/or to achieve the delay of onset of clinical symptoms inpatients with asymptomatic (occult, preclinical) HF due to MVD and/or toachieve the delay of onset of heart failure, preferably congestive heartfailure, in patients with asymptomatic (occult, preclinical) HF due toMVD, when pimobendan is administered in a single dosage form.

In one aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein the asymptomatic (occult, preclinical)heart failure due to mitral valve disease (MVD), preferably asymptomatic(occult, preclinical) congestive heart failure due to mitral valvedisease MVD, more preferably asymptomatic (occult, preclinical)congestive heart failure due to myxomatous mitral valve disease (MMVD)is of stage ISACHC Class I, preferably ISACHC Class IA or Class IB, morepreferably of stage ISACHC Class IB, NYHA Class I and ACVIM stage B2.

In another aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein the pimobendan treatment effects areduction of the heart size of the already pathologically enlarged heartof the patient. In other words, such patient suffers from asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD) ofISACHC Class I (Class IA and/or Class IB), NYHA Class I and ACVIM stageB2 and already has a pathologically enlarged heart (e.g. visible bymeans of echocardiography), but does not yet show any clinical symptomsof heart failure, preferably congestive heart failure.

In another aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein the pimobendan treatment effects aprolongation of the time of survival of the patient as compared toplacebo treatment or non-pimobendan treatment. In this connection,non-pimobendan treatment refers to a comparison treatment where therespective patient group receives an active pharmaceutical ingredientother than pimobendan instead of pimobendan or a placebo. Preferablysuch pimobendan treatment effects a prolongation of the time of survivalof the patient of at least 30 days, more preferably at least 2 months,even more preferably at least 3 months, even more preferably at least 4months, even more preferably at least 5 months, even more preferably atleast 6 months, even more preferably at least 7 months, even morepreferably at least 8 months, even more preferably at least 9 months,even more preferably at least 10 months, even more preferably at least11 months, even more preferably at least 12 months, even more preferablyat least 13 months, even more preferably at least 14 months, even morepreferably at least 15 months, as compared to placebo treatment ornon-pimobendan treatment.

In another aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein the pimobendan treatment effects aprolongation of the preclinical phase without exhibiting clinicalsymptoms of congestive heart failure, effects a delay of onset of(clinical symptoms of) congestive heart failure, increases the survivaltime of the treated patients as compared to placebo treatment, improvesthe quality of life of the treated patients, leads to a reduction ofheart size of the treated patients as compared to baseline (i.e. beforestart of treatment), improves cardiac function/output in the treatedpatients, reduces sudden cardiac death/euthanasia of patients due tocardiac reasons and/or reduces the risk of reaching congestive heartfailure.

In another aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein the patient is a mammal, preferably ahuman, a dog, a cat or a horse, more preferably a dog.

The dosage regimen for pimobendan will, of course, vary depending uponknown factors, such as the pharmacodynamic characteristics and its modeand route of administration; the species, age, sex, health, medicalcondition, and weight of the recipient; the nature and extent of thesymptoms; the kind of concurrent treatment; the frequency of treatment;the route of administration, the renal and hepatic function of thepatient, and the effect desired. A physician or veterinarian candetermine and prescribe the effective amount of the drug required toprevent, counter, delay or arrest the progress of the disorder.

By way of general guidance, the daily oral dosage of pimobendan, whenused for the indicated effects, will range between about 0.2 mg/kg to0.6 mg/kg bodyweight SID, in particular from 0.2 mg/kg to 0.6 mg/kgbodyweight of pimobendan administered per day (EU) and 0.5 mg/kgbodyweight of pimobendan administered per day (US).

Preferably, the daily pimobendan dose is administered as two doses of0.1 mg/kg to 0.3 mg/kg bodyweight, preferably two doses of 0.1 mg/kg to0.3 mg/kg bodyweight every 12 hours (EU), more preferably two doses of0.25 mg/kg bodyweight every 12 hours (USA).

In yet another aspect, the present invention relates to pimobendan foruse according to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein pimobendan is administered in a dailydose of 0.2 mg/kg to 0.6 mg/kg bodyweight SID, in particular from 0.2mg/kg to 0.6 mg/kg bodyweight of pimobendan administered per day (EU)and 0.5 mg/kg bodyweight of pimobendan administered per day (US).

Preferably, the daily pimobendan dose is administered as two doses of0.1 mg/kg to 0.3 mg/kg bodyweight, preferably two doses of 0.1 mg/kg to0.3 mg/kg bodyweight every 12 hours (EU), more preferably two doses of0.25 mg/kg bodyweight every 12 hours (USA).

According to another aspect of the present invention, pimobendan isadministered in combination with at least one second activepharmaceutical ingredient (API). Such at least one second API ispreferably selected from the group consisting of, afterload reducers(arteriodilators) such as ACE inhibitors, preload reducers(venodilators) such as diuretics, platelet inhibitors, beta blockers andangiotensin II antagonists, aldosterone antagonists, antiarrhythmicagents (if arrhythmias occur) and/or diuretics, in particular,

-   -   wherein the ACE inhibitor is selected from the group consisting        of omapatrilat, MDL100240, alacepril, benazepril, captopril,        cilazapril, delapril, enalapril, enalaprilat, fosinopril,        fosinoprilat, imidapril, lisinopril, perindopril, quinapril,        ramipril, ramiprilat, saralasin acetate, temocapril,        trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat        and/or spirapril; and/or    -   wherein the afterload reducer (arteriodilator) is selected from        the group consisting of hydralazine, calcium channel blockers        diltiazem, verapamil, and amlodipine, nitroprusside, and        phosphodiesterase inhibitors such as sildenafil; and/or    -   wherein the beta blocker is selected from the group consisting        of bisoprolol, carvedilol, metoprolol, propranolol, atenolol,        esmolol, and/or timolol; and/or    -   wherein the platelet inhibitor is selected from the group        consisting of aspirin, clopidogrel, factor Xa inhibitors,        heparin, and low molecular weight heparins; and/or    -   wherein the angiotensin II antagonist is selected from the group        consisting of saralasin acetate, candesartan, cilexetil,        valsartan, candesartan, losartan potassium, eprosartan,        irbesartan, tasosartan, pomisartan and/or telmisartan; and/or    -   wherein the aldosterone antagonist is selected from the group        consisting of spironolactone, triampterene, eplerenone,        canrenone, potassium canrenone; and/or    -   wherein the antiarrhythmic agents are selected from the group        consisting of amiodarone, betrylium, disopyramide, dofetilide,        flecainide, ibutilide, mexiletine, tocainide, procainamide,        lidocaine, propafenone, diltiazem, verapamil, digoxin,        digitalis, quinidine and/or sotalol; and/or    -   wherein the diuretic is selected from the group consisting of        furosemide, spironolactone, torasemide, bumetanide, etacrynic        acid, azosemide, muzolimine, piretanide, tripamide,        bendroflumethazide, chlorothiazide, hydrochlorothiazide,        hydroflumethiazide, methychlothiazide, polythiazide,        trichlormethiazide, chlorthialidone, indapamide, metolazone,        quinethazone, etozolin, triamterene and/or amiloride; and/or    -   wherein the preload reducer (venodilator) agents are selected        from the group consisting of nitroglycerine, nitroprusside, and        isorbide; and/or    -   wherein the positive inotropic agents are selected from the        group consisting of dobutamine, digoxin, digitalis, dopamine,        amrinone, and milrinone; and/or    -   wherein the hyperpolarization-activated cyclic nucleotide-gated        (HCN) channel blockers or negative chronotropic agents are        selected from the group consisting of cilobradine, ivabradine,        and adenosine

Preferably, pimobendan is administered together with one or more APIselected from the group consisting of one or more ACE inhibitors and oneor more diuretics.

In yet another aspect, the present invention relates to pimobendan foruse according to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein pimobendan is administered before, duringor after administration of one or more additional active pharmaceuticalingredients selected from the group consisting of ACE inhibitors,preferably benazepril; and diuretics, preferably furosemide. Morepreferably, pimobendan is administered concomitantly with benazepril andfurosemide.

Pimobendan can be administered in such oral dosage forms as tablets,chewable tablets, chews, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, solutions, syrups, and emulsions. Itmay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.It can be administered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

In another aspect, the present invention relates to pimobendan for useaccording to the hereinabove and herein below disclosed aspects andpreferred embodiments, wherein pimobendan is administered orally orparenterally, preferably orally, more preferably orally in the form of atablet or capsule, most preferably orally in the form of a tablet.

Pimobendan can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, usingtransdermal skin patches. When administered in the form of a transdermaldelivery system, the dosage administration will, of course, becontinuous rather than intermittent throughout the dosage regimen.

Pimobendan is typically administered in admixture with suitablepharmaceutical diluents, excipients and/or carriers (collectivelyreferred to herein as pharmaceutical carriers) suitably selected withrespect to the intended form of administration, that is, oral tablets,capsules, elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatine, natural sugars such asglucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

Pimobendan can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

Pimobendan can also be administered in lipid-coated form as part of asolid pharmaceutical formulation (see for instance WO 2015/082389).

Pimobendan may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues.

Furthermore, Pimobendan may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcross linked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit.

In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

Gelatine capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, suitable oil, saline, aqueous dextrose (glucose), andrelated sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where two or more of the foregoing second APIs are administered withpimobendan, generally the amount of each component in a typical dailydosage and typical dosage form may be reduced relative to the usualdosage of the API when administered alone, in view of the additive orsynergistic effect of the APIs when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined APIs. For this reason,when pimobendan and at least one second API are combined in a singledosage unit they are formulated such that although the APIs are combinedin a single dosage unit, the physical contact between the APIs isminimized (that is, reduced). For example, one API may be entericcoated. By enteric coating one of the APIs, it is possible not only tominimize the contact between the combined APIs, but also, it is possibleto control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of the APIsmay also be coated with a material which effects a sustained-releasethroughout the gastrointestinal tract and also serves to minimizephysical contact between the combined APIs.

Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1—Interim Analysis Data

Previous studies have suggested that pimobendan treatment significantlyreduces case fatality and morbidity in dogs with CHF. The potentialbenefit of pimobendan treatment in delaying the progression ofasymptomatic (occult, preclinical) heart failure in dogs due to mitralvalve disease (MVD) has not yet been demonstrated.

Pimobendan is a benzimidazopyridazinone with a potent positive inotropicand a vasodilatory effect. This combined effect of preload and afterloadreduction, together with positive inotropic support, results in areduction in cardiac size and filling pressures in the heart of dogswith occult heart failure due to mitral valve disease.

The administration of pimobendan to dogs suffering from asymptomatic(occult, preclinical) heart failure due to mitral valve disease (MVD)prolongs the time to the onset of clinical signs of congestive heartfailure by approx. 359 days (12.0 months) compared to placebo andextends survival time (all-cause mortality) by approx. 168 days (5.6months) compared to placebo. Treatment of dogs in the preclinical phaseof heart failure with pimobendan therefore leads to improved outcome.

Example 2—Preliminary Analysis of Final Study Results

Preliminary analysis of the final results of a blinded, placebocontrolled study of 360 dogs shows that administration of pimobendan todogs with MMVD and echocardiographic and radiographic evidence ofcardiomegaly results in the prolongation of the preclinical period andis safe and well tolerated.

Median time to the primary endpoint is 1228 days (95% CI 856—NA) in thepimobendan group and 766 days (95% CI 667-875) in the placebo group(P=0.0038). Prolongation of the preclinical period by approximately 15months represents a substantial clinical benefit.

Overall survival, as determined by All Cause Mortality is alsosignificantly longer in the pimobendan group than in the placebo group(P=0.012), and this also represents a significant clinical benefit.

Pimobendan also causes a reduction in heart size, compared to theplacebo group, when measured over the first 35 days of the study(P<0.0001).

The final study results have been published in the meantime (Boswood Aet al., J Vet Intern Med 2016, 30(6): 1765-1779).

REFERENCES

-   (1) Amsallem E et al., Cochrane Database Syst Rev 2005, 25: 1-   (2) Boswood A et al., J Vet Intern Med 2016, 30(6): 1765-1779-   (3) Buchanan J W et al., J Am Vet Med Assoc 1995, 206(2), 194-199-   (4) Chetboul V et al., J Vet Intern Med 2007, 21: 742-753-   (5) EP 0 008 391-   (6) Häggström J et al., J Vet Intern Med 2008, 22: 1124-1135-   (7) Häggström J et al., J Vet Intern Med 2013, 27: 1452-1462-   (8) Lombard C W et al., J Am Anim Hosp Assoc 2006, 42: 249-261-   (9) Ouellet M et al., J Vet Intern Med 2009, 23: 258-263-   (10) Schneider P et al., Exp Toxic Pathol 1997, 49: 217-224-   (11) Summerfield N J et al., J Vet Intern Med 2012, 26: 1337-1349-   (12) Tissier R et al., Cardiovascular Toxicology 2005, 5(1): 43-51-   (13) WO 2005/092343-   (14) WO 2007/054514-   (15) WO 2015/082389-   (16) www.epictrial.com

1. A method for the reduction of heart size and/or delaying the onset ofclinical symptoms in a patient suffering from asymptomatic (occult,preclinical) heart failure due to mitral valve disease (MVD), and/orasymptomatic (occult, preclinical) congestive heart failure due tomyxomatous mitral valve disease (MMVD), and/or delaying the onset ofheart failure in a patient suffering from asymptomatic (occult,preclinical) heart failure due to mitral valve disease (MVD), and/ordelaying the onset of congestive heart failure in a patient sufferingfrom asymptomatic (occult, preclinical) heart failure due to myxomatousmitral valve disease (MMVD) comprising administration of apharmaceutical composition/medicament comprising pimobendan.
 2. A methodfor the reduction of heart size and delaying the onset of clinicalsymptoms in a patient suffering from asymptomatic (occult, preclinical)heart failure due to mitral valve disease (MVD), and/or asymptomatic(occult, preclinical) congestive heart failure due to myxomatous mitralvalve disease (MMVD), and/or delaying the onset of heart failure in apatient suffering from asymptomatic (occult, preclinical) heart failuredue to mitral valve disease (MVD), and/or delaying the onset ofcongestive heart failure in a patient suffering from asymptomatic(occult, preclinical) heart failure due to myxomatous mitral valvedisease (MMVD) comprising administration of a pharmaceuticalcomposition/medicament comprising pimobendan.
 3. The method of claim 1or 2, wherein the asymptomatic (occult, preclinical) heart failure dueto mitral valve disease (MVD), and/or asymptomatic (occult, preclinical)congestive heart failure due to myxomatous mitral valve disease (MMVD)is of stage ISACHC Class I, preferably ISACHC Class IA or Class IB, morepreferably of stage ISACHC Class IB, NYHA Class I and ACVIM stage B2. 4.The method of claim 1, wherein the administration of pimobendan resultsin a reduction of the heart size of the already pathologically enlargedheart of the patient of at least 5%, as compared to a baseline prior topimobendan treatment.
 5. The method of claim 1, wherein theadministration of pimobendan effects a prolongation of the time ofsurvival of the patient as compared to placebo treatment ornon-pimobendan treatment, of at least 30 days.
 6. The method of claim 1,wherein the administration of pimobendan effects a prolongation of thepreclinical phase without exhibiting clinical symptoms of congestiveheart failure, and/or effects a delay of onset of (clinical symptoms of)congestive heart failure, and/or increases the survival time of thetreated patients as compared to placebo treatment, and/or improves thequality of life of the treated patients, and/or leads to a reduction ofheart size of the treated patients as compared to baseline (i.e. beforestart of treatment), and/or improves cardiac function/output in thetreated patients, and/or reduces sudden cardiac death/euthanasia ofpatients due to cardiac reasons, and/or reduces the risk of reachingcongestive heart failure.
 7. The method claim 1, wherein the patient isa mammal selected from the group consisting of: a human, a dog, a cat,or a horse.
 8. The method of claim 1, wherein pimobendan is administeredin a daily dose of 0.2 mg/kg to 0.6 mg/kg bodyweight.
 9. The method ofclaim 8, wherein the daily pimobendan dose is administered as two dosesof 0.1 mg/kg to 0.3 mg/kg bodyweight, wherein two doses of 0.1 mg/kg to0.3 mg/kg bodyweight are administered every 12 hours, or two doses of0.25 mg/kg bodyweight are administered every 12 hours.
 10. The method ofclaim 1, wherein pimobendan is administered orally or parenterally,wherein if administered orally, pimobendan is in the form of a tablet orcapsule.
 11. The method of claim 1, wherein pimobendan is administeredbefore, during or after administration of one or more additional activepharmaceutical ingredients selected from the group consisting of ACEinhibitors, preferably benazepril; and diuretics, preferably furosemide.12. The method of claim 11, wherein pimobendan is administeredconcomitantly with benazepril and/or furosemide.